1. Field of the Invention
The present invention relates to 3'-azido-2',3'-dideoxyuridine (referred to as CS-87 herein) and 3'-azido-2',3'-dideoxycytidine (referred to as DDC herein) and structurally related compounds as agents for prevention and treatment of viral diseases, particularly human immunodeficiency virus (HIV; also known as HTLV-III/LAV), which causes acquired immunodeficiency syndrome (AIDS). The invention is particularly directed to compositions containing 3'-azido-2',3'-dideoxyuridine or 3'-azido-2',3'-dideoxycytidine and to a method of treatment of AIDS which involves treating the person afflicted with this disease with a composition including one of the compounds of the present invention.
2. Brief Description of the Background
AIDS was recognized as early as 1979. The number of cases reported to the Centers for Disease Control (CDC) has increased dramatically each year since then, and in 1982 the CDC declared AIDS a new epidemic. There are now approximately 30,000 reported cases of AIDS, and approximately one-half of those who have contracted the disease have died.
Retroviruses were proposed as the causative agent of AIDS. Two such retroviruses now known to cause AIDS have been identified and isolated: LAV (lymphadenopathy-associated virus) and HTLV-III (human T-cell leukemia virus). It was later determined that LAV and HTLV-III are identical. Antibodies to these viruses are present in over 80% of patients diagnosed as having AIDS or pre-AIDS syndrome, and they have also been found with high frequency in the identified risk groups.
There is considerable difficulty in diagnosing the risk of development of AIDS. AIDS is known to develop in at least 10% of the individuals infected with HIV, although this percentage is suspected to be much higher.
A patient is generally diagnosed as having AIDS when a previously healthy adult with an intact immune system acquires impaired T-cell immunity. The impaired immunity usually appears over a period of eighteen months to three years. As a result of this impaired immunity, the patient become susceptible to opportunistic infections, various types of cancer such as Kaposi's sarcoma, and other disorders associated with reduced functioning of the immune system.
Another condition associated with HIV is AIDS-related complex, or ARC. This condition is thought to lead eventually to AIDS.
No treatment capable of preventing or reversing the immunodeficiency of AIDS or ARC is currently available. All patients with opportunistic infections and approximately half of all patients with Kaposi's sarcoma have died within two years of diagnosis. Attempts at reviving the immune systems in patients with AIDS have been unsuccessful.
Recently, it has been reported that 3'-azido-3'-deoxythymidine (AzT) is an antiviral agent that inhibits the infectivity and cytopathic effect of HIV in vitro. See Mitsuya, et al., Proc. Natl. Acad. Sci. USA 82, 7096-100 (1985). Preliminary results indicate that AzT exhibits toxicity in a clinical setting. See Yarchoan et al., Lancet 575-580 (1986). AzT was originally synthesized by Horwitz et al., J. Org. Chem. 29, 2076-2078, 1964. Its activity against Friend leukemia virus (a retrovirus) was reported as early as 1973 (see Ostertag et al., Proc. Natl. Acad. Sci. USA 71, 4980-4985 (1974) and Krieg et al., Exptl. Cell. Res. 116, 21-29, 1978 and references cited therein). The compounds of this invention are structurally quite similar to AzT, but are remarkably less toxic to normal cells and mice.
In general, inhibitors of cellular processes will often limit viral replication, but such agents are usually quite toxic for the host as well. Most of the antiviral drugs that have been discovered so far cannot be prescribed for a prolonged period of time because of their toxicity. For example, a compound structurally related to the compounds of the present invention, idoxuridine, is limited in clinical usefulness to topical application in ophthalmic solutions for treatment of herpetic keratitis because of its toxicity to normal cells. Clearly, there is a strong demand for new antiviral agents of low toxicity.
CS-87 and DDC are both known compounds. See, for example, Lin et al., J. Med. Chem. 26, 1691-1696 (1983), Lin and Mancini, J. Med. Chem. 26, 544-548, Colla et al., Eur. J. Med. Chem. - Chim. Ther. 295-301 (1985).
Lin et al tested the activity of both CS-87 and DDC against L1210 and sarcoma 180 cells in vitro and found that both of these compounds are inactive against both cell lines. Lin et al also reports that both CS-87 and DDC exhibit only marginal inhibitory activity towards two particular enzymes isolated from L1210 cells. Lin et al does not disclose a composition containing these compounds in a low concentration sufficient to inhibit replication of HIV or even that these compounds could be used to treat HIV.
Lin and Mancini reports that CS-87 and DDC are both inactive against L1210 cells. No other activity for these compounds is reported.
Colla et al reports that CS-87 is inactive against a variety of viruses. In particular, Colla et al reports that CS-87 is inactive against Coxsackie virus B4, polio virus-1, reovirus-1, parainfluenza virus-3, Sindbis virus and measles. Colla et al thus concludes that azido derivatives such as CS-87 do not have significant antiviral activity.
In light of the state of the art, it is clear that there remains a strong need for new antiviral agents, especially those with low toxicity to normal cells. More particularly, because of the high mortality of AIDS and the lack of an effective treatment for this disease, there remains a great need for development of new low toxicity agents for such treatment because AIDS patients require a long term therapy, possibly an entire life span. It was in this context that the present invention was achieved.